After spinal cord injury (SCI) in adult mammals, progenitor cells and astrocytes within the spinal cord divide and migrate to the edge of the lesion site, where they undergo hypertrophy and alter their patterns of gene and protein expression. These responses contribute to formation of a dense glial border, which limits the expansion of inflammatory damage, but also creates a barrier to axonal growth and regeneration. The long term goal of this research program is understand the underlying mechanisms of glial scar formation and identify ways to modify this cellular response in order to improve the prospect of spinal cord repair. The central hypothesis is that spinal cord progenitor cells and astrocytes present in the adult spinal cord are dynamic cells that respond to local cues to change their behavior. Thus, in the presence of an appropriate stimulus, these cells can recruited as active participants for repair and can be stimulated to support growing axons after injury. Prior studies have shown that transforming growth factor alpha (TGFa) can stimulate the proliferation and migration of progenitor cells and astrocytes, and transform astrocytes to a growth supportive phenotype. The objective of this proposal is to determine if targeted activation of the epidermal growth factor receptor with TGF1 will enhance gliogenesis, neuroprotection, and astrocyte migration, and to establish if these responses can be exploited to induce the formation of permissive cellular bridges that will support axonal growth following SCI. The studies in Aim 1 will use loss of function and gain of function approaches to test the hypothesis that EGFR activation facilitates gliogenesis and enhances neuroprotection after SCI. In Aim 2, EGFR activation will be combined with regenerative approaches to test the hypothesis that TGF1overexpression can facilitate the formation of growth supportive glial bridges after SCI. Finally, Aim 3 will employ in vitro and in vivo studies to determine if the effects of TGF1 are modulated by changes in inflammation in acute and chronic SCI. Completion of these aims will define the roles of EGFR activation in glial plasticity and neural repair after injury. These results will provide essential information about the function of cells surrounding the lesion site and serve as an important part of future combination strategies to reduce tissue loss and support axonal growth after SCI. PUBLIC HEALTH RELEVANCE: As many as 1.4 million Americans have some form of paralysis due to injuries sustained in motor vehicle accidents, falls or violence. This research project will determine if cells present in the injured spinal cord can be stimulated to repair the site of injury. Information gained from these studies will contribute to new therapies that will improve recovery, reduce health care costs and allow a better quality of life for spinal cord injured persons in the US and throughout the world.